Project Summary/Abstract: Therapy-induced peripheral neuropathy (TIPN) is a very common and often dose-limiting side effect of anti-cancer therapy. Clinically TIPN is a predominantly sensory peripheral neuropathy characterized by numbness, tingling, and often, neuropathic pain. These symptoms can persist for years after cessation of treatment, and so TIPN can significantly diminish patient's quality-of-life both during and after treatment. Moreover, the development of TIPN often necessitates reducing drug dosage or switching regimens, and therefore limits the effectiveness of anti-cancer therapy. Currently, there are no effective treatments for TIPN. Axon loss is a hallmark of this neuropathy, suggesting that mechanistically distinct chemotherapeutics may feed into a common axonal degeneration program. We have demonstrated that genetic inhibition of this core axonal degeneration program blocks the development of TIPN in a mouse model of vincristine-induced peripheral neuropathy. Now we seek to identify small molecules that can block this axonal degeneration program that could serve as a) chemical probes for the study of axon degeneration and b) therapeutic lead compounds for the development of new treatments to prevent or treat TIPN and other disorders characterized by axon loss. We have developed an assay to identify such inhibitors, and now propose to optimize this assay for a high-throughput screening format. We will use this high-throughput screening platform to conduct a pilot screen and develop a series of counter screens to eliminate false positives and to assess various parameters of identified compounds to prioritize them for further validation. These assays will also serve to characterize mechanistic features of the hits and cluster them based on chemical properties and mechanism of action for biological assays. Finally, we will test the therapeutic potential of identified compounds by examining their activity in cultured neurons using phenotypic axon degeneration assays. If successful, this project will yield a reliable and efficient high-throughput screening platform and follow-up testing funnel for the identification of novel therapeutic candidates for the development of therapies for TIPN and other disorders of the injured and diseased nervous system.